THE METABOLISM OF RETINOIC ACID TO 5,6-EPOXYRETINOIC ACID, RETINOYL-?-GLUCURONIDE, AND OTHER POLAR METABOLITES

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Abstract
A description of the enzyme that produces 5,6-epoxyretinoic acid from all-trans-retinoic acid has been presented. This enzyme system is found in highest concentrations in the kidney followed by intestine, liver and spleen. The enzyme requires molecular oxygen, magnesium ions, ATP, and NADPH. In the kidney, it is found in the mitochondrial and microsomal fractions and has a Michaelis constant of 3.2 X 10(-6) M and 3.7 X 10(-6) M for 13-cis and all-trans-retinoic acid, respectively. The resultant product, 5,6-epoxyretinoic acid, has minimal activity in supporting growth of vitamin A-deficient rats, its activity estimated to be 0.5% that of retinoic acid. An investigation of the biliary excretion products of tritiated retinoic acid has revealed several unknown metabolites. A glucuronidase sensitive metabolite from these products has been isolated and identified as retinoyl-beta-glucuronide by ultraviolet absorption spectrometry and mass spectrometry. The retinoyl-beta-glucuronide originally discovered by Olson and collaborators accounts for only 12% of the total excreted biliary products of retinoic acid. At least four to six major unknown retinoic acid metabolites, in addition to retinoyl-beta-glucuronide, have been detected and will shortly be identified.